Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines individuals as overweight or as suffering from excessive body weight (pre-obese) if their BMI is between 25 and 30 kg/m2, and overtly obese when their BMI is greater than 30 kg/m2. There is increased risk of co-morbidities for individuals with a BMI between 25.0 to 29.9, and moderate to severe risk of co-morbidities for individuals with a BMI greater than 30. Obesity is a serious health and economic burden, and predisposes an individual to a variety of cardiometabolic diseases. Obesity increases the likelihood of metabolic syndrome, hypertension, type 2 diabetes, non-alcoholic fatty liver disease, or obesity-related kidney disease.
Metabolic syndrome is characterized by the presence of three or more of the following components: abdominal obesity (waist circumference>102 cm in men, >88 cm in women), elevated triglycerides (>150 mg/dl or on drug treatment for elevated triglycerides), reduced HDL-C level (<40 mg/dl in men, <50 mg/dl in women or on drug treatment for reduced HDL-C), hypertension (systolic blood pressure>130 mmHg or diastolic blood pressure>85 mm Hg or on antihypertensive drug treatment) and impaired fasting glucose (100-125 mg/dl or on anti-diabetic drug treatment).
Hypertension is a chronic medical condition in which the blood pressure in the vasculature is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Hypertension is present if it is persistently at or above 140/90 mmHg. According to population studies, almost two-thirds of people suffering from obesity are at risk of hypertension.
Diabetes mellitus type 2 (type 2 diabetes) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Obesity is thought to be the primary cause of type 2 diabetes in those people who are genetically predisposed to the disease. Long-term complications from high blood sugar can include heart disease, strokes, diabetic retinopathy where eyesight is affected, kidney failure, and poor circulation of limbs leading to amputations.
Non-alcoholic fatty liver disease includes fatty liver (accumulation of fat in the liver), non-alcoholic steatohepatitis (fat in the liver causing liver inflammation), and often leads to cirrhosis (irreversible, advanced scarring of the liver as a result of chronic inflammation of the liver). All of the stages of non-alcoholic fatty liver disease are now believed to be due to insulin resistance, a condition closely associated with obesity. Moreover, studies demonstrate a correlation between BMI and the degree of liver damage in non-alcoholic fatty liver disease, which shows that the greater the BMI, the greater the liver damage. Non-alcoholic fatty liver disease is an increasingly common liver disease in developed countries because of the rising prevalence of obesity. Elevated transaminases, alanine transaminase (ALT) and aspartate transaminase (AST), are used to monitor non-alcoholic fatty liver disease in obese patients.
Obesity can indirectly influence kidney disease by increasing rates of diabetes and hypertension, which are known risk factors for kidney disease. However, there is growing evidence that obesity per se, even in the absence of diabetes, significantly increases the risk of obesity-related kidney disease and adversely impacts its progression. Obesity-related kidney disease is characterized by albuminuria, glomerulomegaly and secondary focal glomerulosclerosis. Glomerulosclerosis refers to a scarring of the kidneys' tiny blood vessels, the glomeruli, which are the functional units in the kidney that filter urine from the blood. Weight loss, blockade of the renin angiotensin system, and restoration of adipokine levels may be beneficial to ameliorate the progression of obesity-related kidney disease.
Obese Zucker rats (OZRs) have defective brain leptin dependent signal transduction, resulting in markedly increased food intake and decreased energy expenditure. They are used as an animal model of hyperphagia, obesity and associated hyperlipidemia, insulin resistance, fatty liver disease, and renal disease. OZRs are hyperphagic, hyperlipidemic, hyperinsulinemic, and have severe peripheral insulin resistance, metabolic characteristics also seen in human patients with type 2 diabetes and metabolic syndrome. These changes develop during the first 20 weeks of life. OZRs typically die of renal failure, specifically from a glomerular disease pathologically similar to human focal segmental glomerulosclerosis. Various experimental maneuvers have been found to attenuate the development of glomerular disease in OZRs, including treatment with lipid-lowering agents, ovariectomy, and reduction of food intake (Stevenson, F. T., et al., Obesity Research (2001) 9:492-499; Koteish, A., Diehl, A. M., Liver Dis (2001) 21:89-104).
Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several pro-inflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation.
Adipose tissue has a primary role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), namely the central (or upper body) obesity phenotype associated with increased visceral fat. Studies have shown that the amount of intra-hepatocellular lipids increases by approximately 20% for any 1% increase in total or subcutaneous adipose tissue, but doubles for any 1% increase in intra-abdominal adipose tissue. Therefore, even modest increases in visceral fat (in the absence of increased body mass index (BMI)) may cause steatosis (Bugianesi E., et al., Diabetologia (2005) 48:634-642).
Lipomas are adipose tissue tumors, which are benign, slow-growing tumors composed of enlarged adipose tissue cells, preferentially in subcutaneous tissue. They can become painful and the compression derived therefrom on blood vessels may cause neuralgia. Subcutaneous accumulations of fat or proliferations of adipose cells such as lipomas or lipedemas are predominantly treated by surgical means through liposuction or direct surgical removal. Treatment measures of these types are associated with the known complications or risks caused by anesthesia, local reactions and possible infections, and in some circumstances, require admission to a hospital ward. There are currently no FDA-approved injections for the reduction or elimination of local unwanted body fat.
Cellulite is a skin alteration often described as an “orange peel,” “mattress” or “dimpling” appearance on the thighs, buttocks and sometimes lower abdomen and upper arms of otherwise healthy women. Cellulite is caused by small protrusions of fat called papillae adiposae into the dermis. This structural alteration of subcutaneous fat protruding (or herniating) into the dermis gives skin the bumpy appearance referred to as cellulite. Individuals with cellulite and higher BMIs have a weaker, less dense connective tissue structure, leading to increased extrusion of adipose tissue lobules through the hypodermis. These individuals have a higher amount of extrusion of adipose tissue while the thickness of the dermis is significantly lower. Affected individuals with lower BMIs show differences in the thickness of the adipose tissue layer, with a significantly thicker adipose layer in individuals with clinically evident cellulite.